Slide1FIFRAScientificAdvisoryPanelMeetingNewHighThroughputMethodstoEstimateChemicalExposureFIFRAScientificAdvisoryPanelMeetingNewHighThroughputMethodstoEstimateChemicalExposureArlington,VAJuly29‐August1,2014Arlington,VAJuly29‐August1,2014Slide2EPA’sEndocrineDisruptorScreeningProgramEPA’sEndocrineDisruptorScreeningProgramPresentedbyDavidDix,Ph.D.Director,OfficeofScienceCoordinationandPolicyOfficeofChemicalSafetyandPollutionPreventionPresentedbyDavidDix,Ph.D.Director,OfficeofScienceCoordinationandPolicyOfficeofChemicalSafetyandPollutionPrevention1996LegislativeMandate1996FederalFood,DrugandCosmeticAct,section408(p)RequirestheU.S.EPAtodevelopascreeningprogramusingappropriatevalidatedtestsystemsandotherscientificallyrelevantmethodstodeterminewhethercertainsubstancesmayhaveaneffectinhumansthatissimilartoaneffectproducedbyanaturallyoccurringestrogen,orothersuchendocrineeffectastheAdministratormaydesignate.1996SafeDrinkingWaterActAmendments,section1457Testingofchemicalsubstancesthatmaybefoundinsourcesofdrinkingwater,ifsubstantialhumanpopulationsmaybeexposed.Slide3EDSPImplementationEDSPList2Chemicals•DraftEDSPList2chemicalsforTier1screeningreleased(2010)•EPAissuedrevisedEDSPList2with109chemicals(2013)‐Selectionbasedonregistrationreviewscheduleof41pesticidalchemicalsand68drinkingwatercontaminantsEDSPChemicalUniverse10,000chemicals(FIFRA&SDWA)EDSPList2109ChemicalsEDSPList152ChemicalsSlide7EvolutionoftheEDSPBasedoncurrentpaceitcouldtakedecadestoscreenall10,000chemicalsforpotentialtointeractwiththeendocrinesystemRecentadvancesincomputationaltoxicologyheraldanimportant“evolutionaryturningpoint”andanacceleratedpaceofscreeningandtestingToaddressthousandsofchemicalsforpotentialtointeractwiththeendocrinesystem,wemustimplementamorestrategicapproachtoprioritizechemicalsfortargetedscreeningSlide5ScreeningandPrioritizationToxCast•ExpandinguseofCompTox(Phys‐chem properties,QSARS,etc.)tosupportscreeningandprioritization•TransparentandcollaborativeExpoCast•Rapidexposureestimationbasedonreadilyavailablechemicaluseandproductiondata•Usetoxicokinetics tobridgeinvitro,concentration‐basedToxCastdatatoinvivo,dose‐basedExposuresfromExpoCastSlide6ToxCastExpoCastHighThroughputPrioritizationSlide7NewHighThroughputMethodstoEstimateChemicalExposureNewHighThroughputMethodstoEstimateChemicalExposurePresentedbyAlanDixonEndocrineDisruptorScreeningProgramOfficeofScienceCoordination&PolicyOfficeofChemicalSafetyandPollutionPreventionPresentedbyAlanDixonEndocrineDisruptorScreeningProgramOfficeofScienceCoordination&PolicyOfficeofChemicalSafetyandPollutionPreventionIntroductionExposureEstimationwithExpoCast ResearchHighThroughputToxicokinetics(HTTK)andReverseToxicokinetics(RTK)OngoingResearchFutureApplicationsPresentationRoadmapHighThroughputExposureMethodsandReverseToxicokineticsforScreeningandPrioritizationHTEMethodsandRTK•Rapidexposureestimationbasedonreadilyavailablechemicaluseandproductiondata•Usetoxicokinetics tobridgeinvitro,concentration‐basedToxCast datatoinvivo,dose‐basedExposuresfromExpoCastHighThroughputPrioritizationRTKToxCastHTEMethodsToxCast•ExpandinguseofCompTox(Phys‐chem properties,QSARS,etc.)tosupportscreeningandprioritization•TransparentandcollaborativeThisSAPUsingExposureforSettingEDSPPrioritiesEDSTACrecommendation(August1998)“DataresultingfromHTPS[bioactivity/hazard]willbecombinedwithexposure‐relatedinformation,andwithanyothereffects‐relatedinformationthatisavailable,foreachchemicalforthepurposeofsettingprioritiesforT1S”January2013SAPrecommendation(Meetingminutespage24)“AnumberofapproacheswereidentifiedbythePaneltopotentiallyimprovecomparisonsandprioritizationefforts.HTPassayscouldeffectivelybeusedtocategorizechemicalsinatieredmannerorthroughtheuseofadecisiontree.Exposurepotentialcouldbeincorporatedintotherankingandprioritizechemicalsforfurthertesting...”OverallPrioritySettingforEDSPUniverseOtherchemicalsbeyondList1andList2couldhavehigherpriorityforEDSPscreeningandtestingifbioactivityconsiderationsarejoinedwithexposureconsiderationsinanintegratedapproach.Slide10TheNeedforHighThroughputExposureEstimationEDSPUniverseofChemicals•Inventoryofapproximately10,000+ChemicalsthatEDSPhasregulatoryauthority– Basedoncurrentpaceofusinglow‐throughputexposureassessmentmethods(List1andList2)itcouldtakedecadestoprioritizeandscreenall10,000chemicalsforpotentialtointeractwiththeendocrinesystem– Recentadvancesincomputationalexposureestimationcouldbeusedtoacceleratethepaceofestimatingexposuresfromafewchemicalsayeartothousandsofchemicalsayear—acriticalstepinprioritizingandscreeningchemicalsSlide71000067109176EDSPUniverseList1List2FitforPurposeWhatHighThroughputExposure(HTE)IS•WhiletheseHighThroughputExposureexposureestimationmethodsmay– Nothavethetemporalandspacial specificityoftraditionallow‐throughputassessments– Mayonlybewithinanorderofmagnitudeoftraditionallow‐throughputassessments•HTEestimationis“fit”tobeusedtorankchemicalsbasedontheirestimated/predictedexposure.•Thatis,HTEexposureestimatesare“fit”todiscernchemicalswithhigherpotentialexposurefromchemicalswithlowerpotentialexposure.•Thisinturnwillbeconsideredalongwithbioactivitytoprioritizeandscreenchemicalsfortraditionallow‐throughputassessmentmethods.FitforPurpose(continued)WhatHighThroughputExposure(HTE)isNOT•TheHTEestimationmethodspresentedarenotintendedtobepreciseassessmentssimilartotraditionalLowThroughputexposureassessments,e.g.theexposureassessmentsusedinOPP’sRegistrationReviewDecisionsApplicationofExposuretoEDSPPrioritizationAdaptedfromWhitePaper:Section5.FutureApplicationspg.127PotentialExposurefromExpoCastmg/kgBW/dayInvitroBioactivityfromToxCastwithReverseToxicokineticsLowPriorityMedPriorityHigherPriorityIntroductionExposureEstimationwithExpoCast ResearchHighThroughputToxicokinetics(HTTK)andReverseToxicokinetics(RTK)OngoingResearchFutureApplicationsPresentationRoadmapHumanExposureEstimates• FirstGenerationSEEM• SecondGenerationSEEMInprocessSEEMAnalysis• WaterExposureSEEM• ThirdGenerationSEEMforHumanExposure